title: Bone-targeting endogenous secretory receptor for advanced glycation end products rescues rheumatoid arthritis.
abstract: Rheumatoid arthritis (RA) is a chronic inflammatory synovitis that leads to the destruction of bone and cartilage. The receptor for advanced glycation end products (RAGE) is a multiligand membrane-bound receptor for high-mobility group box-1 (HMGB1) associated with development of RA by inducing production of proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1 and IL-6. We developed a bone-targeting therapeutic agent by tagging acidic oligopeptide to a nonmembrane-bound form of RAGE (endogenous secretory RAGE [esRAGE]) functioning as a decoy receptor. We assessed its tissue distribution and therapeutic effectiveness in a murine model of collagen-induced arthritis (CIA). Acidic oligopeptide-tagged esRAGE (D6-esRAGE) was localized to mineralized region in bone, resulting in the prolonged retention of more than 1 wk. Weekly administration of D6-esRAGE with a dose of 1 mg/kg to RA model mice significantly ameliorated inflammatory arthritis, synovial hyperplasia, cartilage destruction and bone destruction, while untagged esRAGE showed little effectiveness. Moreover, D6-esRAGE reduced plasma levels of proinflammatory cytokines including TNF-α, IL-1 and IL-6, while esRAGE reduced the levels of IL-1 and IL-6 to a lesser extent, suggesting that production of IL-1 and IL-6 reduced along the blockade of HMGB1 receptor downstream signals by D6-esRAGE could be attributed to remission of CIA. These findings indicate that D6-esRAGE enhances drug delivery to bone, leading to rescue of clinical and pathological lesions in murine CIA.
authors.affiliation: Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan. t-takahashi@hokuriku-u.ac.jp
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Takahashi
authors.forename: Sayaka
authors.initials: S
authors.lastname: Katsuta
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Tamura
authors.forename: Nozomi
authors.initials: N
authors.lastname: Nagase
authors.forename: Keita
authors.initials: K
authors.lastname: Suzuki
authors.forename: Masaaki
authors.initials: M
authors.lastname: Nomura
authors.forename: Shunji
authors.initials: S
authors.lastname: Tomatsu
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Miyamoto
authors.forename: Shinjiro
authors.initials: S
authors.lastname: Kobayashi
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001172:Arthritis, Rheumatoid; D001224:Aspartic Acid / Q000737:chemistry; D001842:Bone and Bones / Q000378:metabolism*; D002460:Cell Line; D024043:Collagen Type II / Q000276:immunology; D016207:Cytokines / Q000097:blood; D016503:Drug Delivery Systems; D024243:HMGB1 Protein / Q000494:pharmacology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009842:Oligopeptides / Q000008:administration & dosage*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000008:administration & dosage*
chemical_list: D024043:Collagen Type II; D016207:Cytokines; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D009842:Oligopeptides; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D001224:Aspartic Acid